1. Field of the Invention
The invention is directed toward a novel process by which the salts of (xe2x88x92)-hydroxycitric acid, either potassium (xe2x88x92)-hydroxycitrate, the preferred salt of (xe2x88x92)-hydroxycitric acid, or, alternatively, sodium (xe2x88x92)-hydroxycitrate, can be rendered suitable for tableting, encapsulation and use in other dry media for weight loss and other pharmaceutical purposes. Furthermore, the product of this invention can be made nonreactive as a part of acidic drink mixes and acidic snack bars. This invention is further directed toward the production of controlled release versions of potassium or sodium (xe2x88x92)-hydroxycitrate which can be used to provide multi-hour controlled release of the compound.
2. Description of Prior Art
(xe2x88x92)-Hydroxycitric acid (abbreviated herein as HCA) a naturally-occurring substance found chiefly in fruits of the species of Garcinia, and several synthetic derivatives of citric acid have been investigated extensively in regard to their ability to inhibit the production of fatty acids from carbohydrates, to suppress appetite, and to inhibit weight gain. (Sullivan, A. C., et al., American Journal of Clinical Nutrition 1977;30:767.) Numerous other benefits have been attributed to the use of HCA, including, but not limited to an increase in the metabolism of fat stores for energy and an increase in thermogenesis (the metabolism of energy sources to produce body heat in an otherwise wasteful cycle). One commonly offered explanation for the effects of HCA is that this compound inhibits the actions of cytoplasmic (cytosolic) ATP:citrate lyase. (D. Clouatre and M. E. Rosenbaum, The Diet and Health Benefits of HCA (Hydroxicitric Acid), 1994.) Weight loss benefits are ascribed to HCA, its salts and its lactone in U.S. Pat. No. 3,764,692 granted to John M. Lowenstein in 1973. Lowenstein described a variety of possible pharmaceutical salts of HCA based upon alkali metals, e.g., potassium and sodium, and alkaline earth metals, e.g., calcium,. The production of the potassium salt of HCA had been described in the scientific literature previous to Lowenstein""s patent, but not in regard to its weight-loss properties. Research into HCA by scientists at the pharmaceutical firm of Hoffman-La Roche revealed that the lactone form of HCA is far less effective than is the sodium salt of HCA for weight loss purposes, in part because the lactone form lacks the proper affinity for the receptor which is the target of the actions of HCA. However, the sodium salt has disadvantages for long-term administration, both because sodium possesses no positive metabolic effects with regard to obesity and because sodium has potential hypertensive actions as well as other drawbacks. Potassium, as a ligand for HCA, does not possess the disadvantages associated with sodium. Moreover, the absorption of the potassium salt of HCA is considered to be superior to that of the sodium salt owing to the greater rate of uptake of potassium in relation to sodium in most tissues.
Free (xe2x88x92)-hydroxycitric acid, calcium, magnesium and potassium salts of HCA and poorly characterized mixtures of two or more of these minerals, usually substantially contaminated with sodium, currently exist on the American market. Most of the HCA sold consists of calcium salts of varying purity. Aside from the potassium salt, all of these HCA forms suffer from problems in assimilation, a fact attested to by poor performance in controlled weight loss trials. For instance, the free acid form of (xe2x88x92)-hydroxycitric acid is extremely ionic and does not pass readily through the gut membranes. Free HCA has several further disadvantages. It undergoes rapid lacontonization, and, again, the lactone form has no appreciable physiological activity. Indeed, inclusion of any of the currently available mineral salts of HCA in a prepared beverage of acidic pH will lead to the development of the HCA lactone over time. The free acid form, moreover, has a tendency to be bound up and made unavailable to the body by soluble and insoluble fibers as well as by many other compounds. Likewise the potassium and sodium salts, if placed even only briefly in acidic or flavored beverages, typically will undergo color change or exhibit other signs of having undergone chemical interaction with the contents of the beverage. Thus although a patent exists for the use of free (xe2x88x92)-hydroxycitric acid concentrate in food products (U.S. Pat. No. 5,536,516), the art taught therein offers no particular advantages for weight loss nor for other medicinal purposes.
The calcium and magnesium salts of HCA are poorly absorbed from the gastrointestinal tract because they are poorly soluble in aqueous media and because both of these minerals are saponified by bile acids and fats in the gut and/or are bound up by soluble and insoluble fibers or other substances in the diet or secreted during digestion. Some of these problems have been pointed out by medical researchers and admitted in print by at least one primary manufacturer of HCA products. (Heymsfield, Steven B, et al. JAMA 1998;280(18):1596-1600; Letters, JAMA 1999;282:235.) Moreover, there is no evidence that merely making calcium and magnesium salts of HCA more soluble, such as can be accomplished by adding small amounts of potassium and/or sodium and/or lactone, will solve the problem of assimilation. HCA is known to have three separate binding points, and simple chemical experimentation quickly shows that divalent ions, such as those of calcium and magnesium, cannot be readily separated by the application of other acids, such as human gastric acid, from the HCA once these minerals have been reacted with it. The action of stomach acid, however, may free one of the two valences of calcium or magnesium for attachment to fats, bile acids, gums, fibers, pectins, and so forth and so on, which is an undesirable outcome. For weight loss and other purposes, a minimally effective amount of HCA derived from its calcium salt requires the administration of between 12 and 15 grams of a 50% material, and this amount of calcium (xe2x88x92)-hydroxycitrate will lead to undesirably elevated levels of binding and excretion of other dietary minerals, such as zinc, aside from presenting difficulties in administration. Animal trials (not published) have further demonstrated that in order for the potassium salt to be maximally effective, the ligand must be fully bound to the HCA with only minimal amounts of contaminants, including other minerals or fibers or sugars. Hence the calcium and magnesium salts, either alone or in the form of various mixtures together or in combination with the potassium and sodium salts, are not preferred delivery forms for HCA.
The preferred salt of HCA for pharmaceutical use is potassium (xe2x88x92)-hydroxycitrate (abbreviated herein as KHCA). The mineral potassium is fully soluble, as is its HCA salt, and is known to possess cell membrane permeability which is 100 times greater than that possessed by sodium. However, the potassium salt of HCA, as is also true of the sodium salt, is extremely hygroscopic and thus not suitable under normal circumstances for the production of dry delivery forms. In drawing moisture to itself, KHCA will also tend to bind to available binding sites of compounds in its immediate environment, and this action often later will markedly impede the assimilation of KHCA from the gut. KHCA is also not suitable for liquid delivery forms inasmuch as KHCA in solution, will slowly lactonize to an equilibrium which is dependent upon the pH. One recent patent (U.S. Pat. No. 5,783,603) does teach a technique for the production of KHCA, but this material is nonhygroscopic only under the conditions mentioned specifically in that patent, to wit, xe2x80x9cmilling, sifting, blending and packing said dried precipitate under nitrogen to obtain said potassium hydroxycitric acid [sic] composition.xe2x80x9d If left in the open air outside of a humidity-controlled environment, the KHCA produced according to that patented method will begin to absorb moisture within a few minutes. Except as a very minor ingredient, it cannot be used as a component of dry pharmaceutical or nutriceutical preparations. Hence, no prior art teaches the production of the relatively pure potassium salt of (xe2x88x92)-hydroxycitric acid in a form which is workable under those conditions necessary for tableting, encapsulation, the production of controlled release vehicles nor incorporation into dry powders, such as dry meal replacement mixes. No prior art teaches a method of including potassium or other forms of HCA in liquid media without lactonization and no prior art teaches a method by which KHCA may be delivered under controlled release. Likewise, no prior art teaches the above with regard to sodium (xe2x88x92)-hydroxycitrate.
Furthermore, the lack of a method of producing a controlled release form of HCA, regardless of the salt used, has led to a problem in the delivery of the drug. Tests performed to establish the appetite-suppressing effects of HCA found that a single large oral dose or two divided oral doses totaling one fourth the size of the single dose resulted in a 10% or greater reduction in food consumption in experimental animals fed a high-sugar diet. This result continued over many weeks with the chronic ingestion of HCA. The requirement for at least two divided doses of HCA for efficacy is the only thoroughly established procedure to date.
Giving HCA as multiple doses, as is true of any drug, is inconvenient and is not supported by good patient compliance. Multiple doses given in the form of any of the current salts is also wasteful in that any material delivered to the body which is above the baseline or threshold necessary to produce benefits is simply an excess which is excreted. Controlled release of HCA would avoid both excess and waste, on the one one, and gaps in coverage, on the other hand. Controlled release makes it possible to simplify the dosage schedule to one daily administration. Moreover, it is to be expected that a smaller amount of HCA delivered by controlled release will provide benefits which are superior to those found with a larger amount of HCA supplied after a normal fashion in at least two dosages.
The present invention resolves the problems described above with regard to the use of the potassium and sodium salts of (xe2x88x92)-hydroxycitric acid. The principle is provided by which the hygroscopic salts of (xe2x88x92)-hydroxycitric acid in their relatively pure and active forms, including especially the potassium salt, but also including the sodium salt, are rendered non-hygroscopic and stable (that is, not prone to lactonization, not readily subject to attachment to ligands which inhibit absorption or lead to excretion, and so forth as described previously) such that these HCA salts might be included in dry delivery formats, liquid delivery and in controlled-release vehicles. Moreover, the nonhygroscopic salts of (xe2x88x92)-hydroxycitric acid may also be protected against acid degradation, lactonization and undesirable ligand binding when exposed to acidic environments or other challenging conditions.
Objects and Advantages
The potassium salt of (xe2x88x92)-hydroxycitric acid is the most efficacious form of HCA to be used for human weight loss and for other pharmaceutical and/or neutraceutical purposes, followed secondarily for these purposes by the sodium salt. The potassium and the sodium salts of HCA present very similar difficulties in handling and manipulation. Potassium (xe2x88x92)-hydroxycitrate is extremely hygroscopic and tends to bind with water in the open air to form a non-palatable paste not suitable for use in tablets, capsules or powders. This material can be admixed with orange juice or water, but requires vacuum pouch sealing under a humidity-controlled atmosphere and is inconvenient for the patient to use. KHCA, moreover, is reactive with a large number of compounds (tannins, gums, fibers, pectins, and so forth) are thereby readily suffers large losses in pharmacological availability.
Using acceptable, yet novel pharmaceutical art forms for this product, the inventors have been successful in granulating the potassium salt form of (xe2x88x92)-hydroxycitric acid extract into a fine coated powder which is acid resistant and which retards water inclusion into the material. This has been accomplished by coating the particulate material with an acid retardant film and then exposing the product to a high heat environment which produces a dry ( less than 3% moisture) white powder which can be compressed into a tablet, used to fill a hard gelatin capsule or admixed into a viscous flavored drink or into a meal replacement or acidic snack bars. By using an acid retardant coating, we prevent exposure to possibly binding compounds prior to ingestion and also in the stomach and upper gastrointestinal tract above to the point at which the KHCA can be absorbed. We thus allow for the optimum absorption of the KHCA in the small intestine. The polymer film acts as a water barrier which allows for various forms of pharmaceutically acceptable preparations to be prepared from the raw material. The method described applies to the potassium salt of (xe2x88x92)-hydroxycitric acid; with minor revisions it can be applied to the sodium salt, to mixtures or combinations of the two salts, and to combinations of these salts in which calcium or magnesium (xe2x88x92)-hydroxycitrate are additions. The treated material produced according to our discovery can further be used to produced controlled release dosage forms with their many inherent biologic advantages, including the possibility of reducing intake of the compound to one daily administration.
The raw material is the potassium salt of (xe2x88x92)-hydroxycitric acid which has been produced from the aqueous extract of Garcinia cambogia, other Garcinia species or by synthesis. In hydrated form, it is a viscous deep brown. It has a earthy smell and contains approximately 6 parts by weight of solids per liter of fluid. The novel concept is to encase the potassium salt of (xe2x88x92)-hydroxycitric acid with an acidophobic and hydrophobic polymer after driving off the water from the raw material. The polymer employed will not bind to the ligand sites of the raw material. This procedure results in a material which is resistant to water and acid media. Moreover, by so coating the raw material, it becomes possible to easily work with it for the production of pharmaceutical formulations of various types and nature, to form it into edible bars, drinks, and other marketable forms of the basic substance. In addition, when the treated material is ingested, it resists degradation by the acid of the upper intestinal tract. Treatment allows for a prolonged release time in the more basic pH of the small intestine, and this, in turn, allows for a slow and steady diffusion of the active ingredient across the gut wall.
Methods Of Preparation
In essence the potassium salt of (xe2x88x92)-hydroxycitric acid is made aqueous by the addition of deionized water by bringing the volume to 5 L of water. In a separate container 1 L of deionized water is ammoniated with approximately 1,000 mL of 28% ACS ammonium hydroxide and stirred. Into the KHCA is added 1 kg of maltodextrin and the mixture of maltodextrin and KHCA is stirred with a medium propeller mixer. Into the 1 L of ammonium hydroxide is added 5 gm of cellulose acetate phthalate (CAP), which is the polymer for encasement. The CAP is then slowly poured into the blending KHCA and maltodextrin; deionized water is added until the weights/water are 24-25%. This thoroughly admixed solution is then passed into a spray dry chamber at 265xc2x0 C. using a Watson Marlow pump and a flow rate at 1-2 L/minute. The powder is an off white dusk color and is collected in the collection bowl until all the fluid has been passed through the pump. The powder contains about 35% of KHCA by weight. When left in an open plastic boat there is no evidence of hygroscopic interaction after 1 week with a relative humidity of 70%. The powder showed no signs of degradation or discoloration after this time. To allow the powder to flow without sticking, magnesium stearate is added for capsule filling or tableting. With the proper revisions by one skilled in the art, this procedure can be applied readily to potassium, sodium or other salts of (xe2x88x92)-hydroxycitrate to be processed via fluid bed dryer.